The Alzheimer's Disease Research Center (ADRC) at Johns Hopkins University (JHU) consists of 5 Cores: (1) the Administrative Core; (2) the Clinical Core; (3) the Data Management and Statistics Core; (4) the Neuropathology Core; and (5) the Education Core. These Cores interact with each other, in order to stimulate and support Alzheimer's disease (AD) research throughout JHU. In the current funding cycle, ADRC investigators have published 324 peer-reviewed articles and 24 chapters on aging and age-related degenerative disorders. Of these, 108 peer-reviewed publications are directly related to projects supported by the involvement of ADRC subjects. The ADRC has been associated with 21 projects that have been supported by the enrollment of ADRC subjects and 31 projects that have been supported by the provision of brain tissue or other specimens. In the next funding cycle, Center funds will directly support three research Projects: Project 1 (PI - Dr. R. O'Brien) - The roles of amyloid, tau, and synaptic loss in early AD; Project 2 (PI - Dr. A. Savonenko) - Modeling an anti-amyloid therapy for AD: potential for cognitive recovery and Project 3 (PI - Dr. P. Wortey) - Neuronal activity-dependent secretion of A and immediate early genes. Each of the Projects is consistent with the guidelines of the RFA: Project 1 takes advantage of brain tissue collected over many years from well characterized subjects in the ADRC (through the collaboration of the Clinical Core and the Neuropathology Core); Project 2. led by a junior investigator, focuses on manipulations of levels of A species and its influence on behavior and brain biology; and Project 3. led by a senior investigator who is new to the AD field, but whose research on the influences of specific gene products, especially the roles of immediate early genes on synaptic functions, is highly relevant to AD. Together with the large number of associated projects supported by the ADRC, the Center focuses on two Interrelated themes: (1) characterization and understanding of the early clinical and pathological stages of AD in humans; and (2) the identification of the cellular and molecular events that contribute to the clinical abnormalities in animal models. Thus, as in the previous funding cycle, the focus of this application will be on the earliest stages of pathology in humans and in model systems, with the goal of influencing the development of experimental therapeutics that, when introduced Into the clinic, can delay or prevent AD.